Process and intermediates for manufacture of 16-oxa steroids



3,309,383 PROCESS AND KNTERMEDKATES FOR MANU- FACTURE F lie-SKA STEROIDS Raphael Pappo, Slrokie, Ill., assignor to G. D. Searle & Co., Chicago, ML, a corporation of Delaware No Drawing. Filed Feb. 17, 1966 Ser. No. 528,104 14 Claims. (Cl. 260343.3)

The present invention is concerned with a novel process and novel intermediates useful for the manufacture of 16-oxa steroids and the corresponding hydroxy acids. The 16-oxa steroids and hydroxy acids especially contemplated are hypocholesterolemic agents which possess the particular advantage of lacking estrogenic side-effects and are represented by the following structural formulas (lower alkyl) (lower alkyl) 0 and (lower alkyl) C O O H l CH2OH (lower allryl) 0 wherein X is a carbonyl, hydroxymethylene or (lower alk)-oxymethylene radical.

The lower al-kyl radicals encompassed in the foregoing structural representation are methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl and the branched-chain groups isomeric therewith.

In the initial step of the instant process, a 6-(lower alkoxy)-1-vinyl-l-tetralol represented by the following structural formula (lower alkyl) O is contacted with a 2-(lower alkyl)-4-oxacyclopentane- 1,3-dione of the following structural formula (lower alkyl) 0 l 1 optionally in the presence of an alkaline catalyst to afford an intermediate illustrated by the formula (lower alkyl) (lower alkyl) 0 Alkaline catalysts particularly suitable for this purpose are strongly basic organic tertiary amines such as tri- Patented Mar. 14, 1967 iQQ (lower alkyl) by heating in an inert organic solvent medium in the presence of a strong acid catalyst. The aforementioned 2-methyl-2-(6-methoxy-l-naphthyliden)ethyl 4 oxacyclopentane lfl-dione is thus refluxed in benzene solution in the presence of p-toluenesulfonic acid to yield 3- methoxy-16-oxaestra-1,3,5 10),8 (9 14-pentaen-17-one.

Selective reduction of the 14 (l5) double bond of the latter pentaenes is suitably effected by catalytic hydro-- genation, thus providing the corresponding tetraenes represented by the following formula lower alkyl( (lower alkyl) O That process is specifically illustrated by the hydrogenation, at atmospheric pressure and room temperature, of 3-methoxy-16-oxaestra-1,3,5(1'0),8(9),l4 pentaen 17- one, in the presence of a catalytic quantity of 5% palladium-on-carbon, to aiford 3 methoxy 16 oxaestra- 1,3,5 10) ,8 (9)-tetraen-l7-one.

The lactone ring of the latter intermediates is conveniently opened by reaction in aqueous medium with an alkali metal hydroxide or suitable weak acid salt to afford the corresponding hydroxy acid alkali metal salts illustrated below:

(lower alkyl) C O O M (lower alkyl) O wherein M is an alkali metal cation. When 3-methoxy- 16-oxaestra1,3,5(1-O),8(9)-tetraen-17-one is heated with sodium carbonate in aqueous methanol the sodium salt of trans-Z-carboxy-l-hydroxymethyl-Z-methyl 1,2,3,4,9,10- hexahydrophenanthren-7-ol 7-methyl ether is obtained.

The 4a(10a) double bond of the latter alkali metal salts v or of the corresponding free hydroxy acids is preferen- 3 tially reduced when those intermediates are contacted with an alkali metal and liquid ammonia, optionally in the presence of aniline, thus producing intermediates of the following formula (lower alkyl) C OX CH2OH (lower alkyl) 0 wherein X is hydrogen or an alkali metal cation. The sodium salt of trans-Z-carboxy 1 hydroxy'methyl 2- rrrethyl-1,2,3,4,9,10 hexahydrophenanthren-7-ol 7-1methyl ether is thus stirred with metallic sodium and liquid ammonia containing aniline to yield, after acidification, trans 2 carboxy l hydroxymethyl 2 methyl- 1,2,3,4,4a,9,10,ltla-octahydrophenanthren-7-ol 7 methyl ether.

Cyclization of the latter hydroxy acids to afford the desired l6-oxa compounds of the following formula (lower alkyl) (lower alkyDO (lower alkyl) "OOOM (lower alky1)0 A specific illustration is the reaction of 3-methoxy-l6- oxaestra-1,3,5(l-0),8 (9),14-pentaen 17 one with potassium carbonate in aqueous ethanol to yield the potassium salt of trans 2 carboxy-l-formyl-Z-methyl-1, 2,3,4,9,10- hexahydrophenanthren-7-ol 7- methyl ether. Reduction of those aldehyde-acids with a suitable reducing agent affords the above described hydroxy acids of the following formula (lower alkyl) O O O H CH2OH (lower alkyl) 0- which are converted to the corresponding 1-6-oxaestra- 1,3,5(10)-trien-17-ones as described hereinbefore.

An additional alternative variation in the present process involves reduction of the 17-keto group of the aforementioned 3-(lower alkoxy)-l3fi-(lower alky1)16-oxagona-l,3,S (l0), 8 (9)-tetraen-17-ones to yield the corresponding 17-ols, etherification of the 17-hydroxy group by reaction with a lower alkanol in the presence of an acid catalyst and reduction of the 8(9) double bond by the alkali metal-liquid ammonia-aniline method described hereinbefore to produce the desired 13,8-(lower alkyl)- 16 oxagona 1,3,5 (10)-triene-3,l7-diol 3,17-di-(lower al-kyl) ethers of the following formula (lower alkyl) (2) (lower alkyl (lower alkyl) 0- wherein the wavy line indicates the alternative (1 or ,8 stereochemical configuration. The 17-(lower alkoxy) group can be cleaved by reaction with a dilute mineral acid in a suitable organic solvent medium to afford the corresponding l7-ols. Those procedures are illustrated by the low temperature reduction of 3-methoxy-16-oxaestra-1,3,5(10),8 (9)-tetraen-l7-one with diisobutyl aluminum hydride in toluene, reaction of that 17-01 with methanol in the presence of p-toluenesulfonic acid and reduction of the resulting 17-ol l7-methyl ether by means of sodium and liquid ammonia containing aniline to afford 16 oxaestra-l,3,5(10)-trien-3,l7-diol-3,l7-dimethyl ether. Heating of the latter substance with dilute hydrochloric acid in tetrahydrofuran solution yields 3- methoxy-l6-oxaestra-1,3,5'(10)-trien-.17-ol.

The intermediates of the present invention are obtained in the form of their dl-mixtures. Those enantiomorphic mixtures can be resolved however by methods known to the art. Those derivatives containing a carboxylic acid group, for example, form salts with optically active amines such as brucine, cinchonine, menthylamine, morphine, quinidine, quinine and strychnine. Fractional crystallization of the resulting diasteriomeric salts followed by regeneration of the free acids affords the individual d and l enantiomorphs.

The following examples illustrate in further detail some of the compounds which constitute this invention together with methods for their preparation. The invention, however, is not to be construed as limited thereby either in spirit or in scope as many modifications both in materials and methods can be adapted without departing from the invention herein described. In these examples, temperatures are indicated in degrees centigrade C.) and quantities of materials in parts by weight unless otherwise noted.

EXAMPLE 1 To a solution of 20.4 parts of 6-methoxy-1-vinyl-ltetralol in 92 parts of toluene is added successively 10.2 parts of triethylamine and 10 parts of 2-methy1-4-oxacyclopentane-1,3-dione. The resulting reaction mixture is heated at the reflux temperature in a nitrogen atmosphere for about 4 hours, during which time the water of reaction in azeotropically removed. The mixture is then partially concentrated by distillation over a period of about one hour, then is cooled and diluted with benzene. The resulting organic solution is washed successively with 5% aqueous potassium bicarbonate and water, then dried over anhydrous sodium sulfate and distilled to dryness under reduced pressure. The resulting gummy residue is purified by crystallization from isopropyl alcohol-ether to afford dl-2-methyl 2-1( 6-methoxy-l-naphthyliden)ethyl 4 oxacyclopentane-l,3-dione, which dis- 5 plays a melting point at about 86-87. This compound is represented by the following structural formula EXAMPLE 2 A mixture containing 4 parts of dI-2-methyl-2-(6-methoxy 1 naphthyliden)ethyl-4-oxacyclopentane-1,3-dione and 0.1 part of p-toluenesulfonic acid in 106 parts of dry benzene is heated at the reflux temperature for about 15 minutes, in a nitrogen atmosphere, while the water of reaction is mechanically removed. The reaction mixture is then cooled to 0-5, washed successively with water and aqueous potassium bicarbonate, then dried over anhydrous sodium sulfate. Removal of the solvent by distillation under reduced pressure affords a gummy residue which is crystallized from benzene-ether to yield dl-3- methoxy 16-oxaestra-1,3,5(l0),8'(9),14-pentaen-17-one, melting at about 151153. It can be represented by the EXAMPLE 3 To a solution of one part of dl-3-methoxy-16-oxaestra- 1,3,5 (l0),8(9),14-pentaen-17one in 132 parts of benzene is added 0.1 part of 5% palladium-on-carbon catalyst, and the resulting mixture is shaken with hydrogen at atmospheric pressure and room temperature until one molecular equivalent of hydrogen has been adsorbed. The mixture is then filtered to remove the catalyst, and the filtrate is concentrated under reduced pressure to afford the crude product. Recrystallization of that solid residue from benzene-ether affords dl-El-methoxy-16-oxaestra1,3, 5(10),8(9)-tetraen17-one, melting at about 139-448. Two additional recrystallizations from benzene-ether affords the pure material, displaying a melting point at about 156-159. This compound is illustrated by the following structural formula CHaO- i EXAMPLE 4 material is extracted with anhydrous methanol, and the insoluble inorganic salts are removed by filtration. Concentration of the filtrate to dryness by distillation under reduced pressure affords the crystalline sodium salt of 0 stirred for about one hour.

moved by evaporation under nitrogen.

70 subsides.

dl trans 2-carboxy-1-hydroxymethyl-2-methy1-1,2,3,4, 9,10-hexahydrophenanthren-7-ol 7-methy1 ether. This compound is represented by the following formula GHaO \J "COONa 0 dl trans 2-carboxy-1-hydroxymethyl-2-methyl 1,2,3,4,

9,l0-hexahydrophenanthren-7-ol 7-methyl ether, melting at about 187-190 with decomposition.

EXAMPLE 5 To a solution of 2 parts of the sodium salt of dl-trans- 2-carboxy-l-hydroxymethyl 2 methyl l,2,3,4,9,1-0- hexahydr-ophenanthren-7ol 7-methyl ether in 140 parts of liquid ammonia is added one part of metallic sodium and 13 parts of aniline, and the resulting reaction mixture is Approximately 4 parts of solid ammonium chloride is added, and the solvent is re- The resulting residue is diluted with water, and the aqueous solution thus obtained is washed with benzene, then acidified to pH 5 with cooling, thus affording dl-trans-Z-ca-rboxy-lhydroxymethyl 2 methyl-1,2,3,4,4a,9,10,IOa-octahydnophenanthren-7-o1 7-methyl ether.

EXAMPLE 6 A mixture of one part of dl-trans-2-carboxy-l-hydroxymethyl 4 2 methyl 1,2,3,4,4a,9,10,10a octahydrophenanthren-7-ol 7-methyl ether, 001 part of p-toluenesulfonic acid monohydrate and 264 parts of benzene is distilled until approximately 88 parts of benzene is collected. Cooling of the reaction mixture to room temperature followed by washing with dilute aqueous sodium bicarbonate, and drying over anhydrous sodium sulfate affords an organic solution, which is concentrated to dry- A mixturecontaining 2.74 parts of dl-3-methoxy-l6- oxaestra-l,3,5(l0),8(9),14-pentaen-l7-one, 1.36 parts of potassium carbonate, 120 parts of ethanol and 50 parts of water is heated at the reflux temperature under nitrogen for about 3 hours, then is cooled and concentrated to dryness to afford a mixture of the potassium salts of dl-transl -carboxy-l-forrnyl 2 methyl-1,2549,1'0-hexahydrophenant-hren-7-ol 7-methyl ether and dl-cis-Z-carboxy-lformyl-Z-methyl 1,2,3,4,9,10 hexahydrophenanthren-7- o1 7-methyl ether.

To a solution of one part of sodium borohydride in 50 parts of ethanol is added slowly, with stirring, one part of the latter mixture of potassium salts, and the reaction mixture is diluted with water after the initial reaction The resulting solution is stirred at room temperature for about 5 hours, then is made acidic by the addition of dilute hydrochloric acid. The precipitate which forms is extracted into chloroform, and the chloroform solution is extracted with dilute aqueous potassium bicarbonate. Evaporation of the organic solution to dry- 7 ness affords dl 3 methoxy-l6-oxa-14B-estra-1,3,5(10), 8 (9) -tetraen-17-one.

Acidification of the potassium bicarbonate extract with dilute hydrochloric acid results in formation of a precipitate which is isolated by filtration to produce dl-trans- 2-carboxy-1-hydroxymethyl-Z-methyl-1,2,3,4,9,1O hexahydrophenanthren-7-ol 7-methyl ether.

EXAMPLE 8 EXAMPLE 9 To a solution of 2 parts of dl-3-meth-oxy-16-0xaestra- 1,3,5 (10),8(9)-tetraen-17-one in 87 parts of dry toluene is added, at 70, 5.25 parts by volume of a 25% solution of diisobutyl aluminum hydride in toluene. The resulting reaction mixture is stirred at that temperature for about one hour, then is poured carefully, with stirring, into a mixture of 100 parts of water and 200' parts of ice containing 42 parts of acetic acid. The organic layer is separated, washed successively with water and saturated aqueous sodium bicarbonate, dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure to afford dl-3-methoxy-16-oxaestra-1,3,5(1-O),8(9)- tetraen-17-ol.

EXAMPLE 10 To a solution of 2 parts of dl-3-methoxy-16-oxaestra- 1,3,5 (10),8(9)-tetraen-17-ol in 40 parts of methanol is added 0.05 part of p-toluenesulfonic acid rnonohydrate. The precipitate which forms is isolated by filtration and dried to afford d-16-oxaestra 1,3,5 (10),8(9)-tetraene- 3,17-diol-3, 17-dimethy1 ether.

EXAMPLE 1 1 When an equivalent quantity of dl-16-oxaestra-L3, (),'8(9)-tetraene-3,17-diol 3,17-dimethyl ether is substituted in the procedure of Example 5, there is produced dl-16-oxaestra-1,3,5(10) triene-3,l7 diol 3,17-dimethyl ether.

EXAMPLE 12 A mixture containing 2.5 parts of dl-16-oxaestra- 1,3,5 (1'0)-triene-3,17-diol 3,17-dimethyl ether, 135 parts of tetrahydrofuran and 50 parts by volume of 0 .5 N bydnochloric acid is concentrated to approximately one-half volume by distillation over a period of about 45 minutes. The residual aqueous mixture is neutralized by the addition of dilute aqueous sodium bicarbonate, then is extracted with chloroform. The resulting chloroform solution is dried over anhydrous sodium sulfate, then is stripped of solvent by distillation under reduced pressure to afford dl-3-methoxy-16-oxaestra-1,3,5 10) -trien-17-ol.

EXAMPLE 13 When equivalent quantities of 6-ethoxy-1-vinyl-1-tetral-ol and 2-ethyl-4-oxacyclopentane-1,3-dione are substituted in the procedure of Example 1, there is produced dl-2-ethyl-2-(6-ethoxy-1-naphthyliden)ethyl 4 ox acyclo pentane-1,3-dione.

EXAMPLE 14 When an equivalent quantity of dl-2-ethyl-2-(6-ethoxyl-naphthyliden)ethyl-4-oxacyciopentane-1,3-dione is substituted in the procedure of Example 2, there is produced 8 dl-3-eth-oxy-13/3-ethyl 16 oxagona 1,3,5(10),8(9),14- pentaen-17-one.

EXAMPLE 15 By substituting an equivalent quantity of dZ-3-ethoxy- 13fl-ethyl-16-oxagona 1,3,5 10),8(9),14-pentaen-17one and otherwise proceeding according to the processes described in Example 3, there is produced dl-3-ethoxy-l3B- ethyl-16-oxagona-1,3,5(10),8(9)-tetraen-17-one.

EXAMPLE 16 The substitution of an equivalent quantity of a l-3- ethoxy 13,8-ethyl-16-oxagona-1,3,5(10),8(9)-tetraen-17- one in the procedure of Example 4 results in the sodium salt of dl-trans-Z-carboxy-l-hydroxymethyl-Z-ethyl-1,2,3, 4,9,10-hexahydrophenanthren-7-ol 7-ethyl ether and also the corresponding free hydroxy acid.

EXAMPLE 17 When an equivalent quantity of the sodium salt of dltrmns-Z-carboxy 1 hydroxymethyl-Z-ethyl-1,2,3,4,9,10- hexahydrophenanthren-7-ol 7-ethyl ether is substituted in the procedure of Example 5, there is obtained dl-trans-Z- carboxy-l-hydroxymethyl 2 ethyl-1,2,3,4,4a,9,l0,10aoctahydrophenanthren-7-ol 7-ethyl ether.

EXAMPLE 1 8 When an equivalent quantity of dl-trans-Z-carboxy-lhydroxymethyl-Z-ethyl 1,2,3,4,4a,9,10,l0a octa-hydrophenanthren-7ol 7-ethyl ether is substituted in the procedure of Example 6, there is obtained dl-3-ethoxy-13fiethyl-16-oxagona- 1,3,5 10 -trien-17-one.

EXAMPLE 19 The substitution of an equivalent quantity of S-ethoxy- 13fl-ethyl 16 oxagona-l,3,5(1'0),8(9'),14-pentaen-17- one in the procedures of Example 7 afiords dl-tralns-Z- carboxy 1 formyl 2 ethyl 1,2,3,4,9,10-hexahydrophenanthren-7-ol 7-ethyl ether, dl-cis-Z-carboxy-1-formyl 2-ethyl-1,2,3,4,9,10-hexahydnophenanthren 7 ol 7-ethyl ether, dl-3-ethoxy-13,8-ethyl-16-oxa-14fl-gona 1,3,5 (10), 8(9) tetraen-17-one and dl-trans-Z-carboxy-l-hydroxymethyl 2 ethyl-1,2,3,4,9,10-hexahydrophenanthren-7-ol 7-ethyl ether.

EXAMPLE 20 When an equivalent quantity of dl-3-ethoxy-13fi-ethyl- 16-oxagona-1,3,5(10),8(9),14-pentaen-17-one is substituted in the procedure of Example 8, there is produced dl 3 ethoxy-13,8-ethyl-16-oxa-14fi-gona-1,3,5(10),8(9)- tetraen-l7-one.

EXAMPLE 21 The substitution of an equivalent quantity of dl-3- ethoxy-13 8-ethyl-16-oxagona-1,3,5(l0),8(9)-tetraen 17- one in the procedure of Example 9 results in dl-3-ethoxy- 13B-ethyl-16-oxagona-L3 ,5 10) ,8 (9 -tetraen-17-ol.

EXAMPLE 22 When an equivalent quantity of dl-3-ethoxy-13fi-ethyl- 16-oxagona-1,3,5(10),8(9)-tetraen-17-ol is substituted in the procedure of Example 10, there is obtained dl-3- ethoxy--ethyl-16-oxagona-1,3,5( l0),8(9)-tetraen 17- 01 17-methyl ether.

EXAMPLE 23 The substitution of an equivalent quantity of dl-3- ethoxy-13 B-ethyl-16-oxagona-1,3,5( 10) ,8 (9 -tetraen 17- 01 17-methyl ether in the procedure of Example 5 results in dl-3-ethoxy-13/3-ethyl-16-oxagona- 1,3,5 10)-trien-17-0l 17-methyl ether.

EXAMPLE 24 When an equivalent quantity of dl-3-ethoxy-13B-ethyl- 16-0Xag a- ,3,5(10)-trien-17-ol 17-methyl ether is substituted in the procedure of Example 12, there is produced dl-3-ethoxy-13fi-ethyl-16-oxagona-1,3,5 (l)-trien 17 ol.

EXAMPLE 2s The substitution of an equivalent quantity of til-3- methoxy-l6-oxaestra-1,3,5(10)-trien-l7-one in the procedure of Example 9 results in dl-3-methoxy-16-oxaestra- 1,3,5 (l0)-trien-17-ol which, after recrystallization from acetone, melts at about 148-149 and is identical with the product of Example 12.

What is claimed is:

1. The process which comprises contacting a 6-(lower alkoxy)-l-vinyl-l-tetralol with a 2-(lower alkyl)-4- oxacyclopentane-l,3-dione, heating the resulting 2- (lower alkyl)-2-[(6-lower alkoxy)-l-naphthyliden1ethyl 4-oxacyclopentane-1,3-dione with an acidic reagent, contacting the resulting 3-(lower alkoxy)-13fi-(lower 'alkyl)-16- oxagona-1,3,5(10),8(9),14-pentaen-17-one with hydro gen in the presence of a hydrogenation catalyst, contacting the resulting 3-(lower alkoxy)-l3p-(lower alkyl)-l6- oxagona-1,3,5(l0),8(9)-tetraen-l7-one with an alkali metal hydroxide or suitable weak acid salt, contacting the resulting alkali metal salt of a trans-Z-carboxy-l-hydroxymethyl-Z- (lower alkyl) 1,2,3 ,4,9, l0-hexahydrophenanthren-7-ol 7-(lower alkyl) ether or'the corresponding free acid with an alkali metal and liquid ammonia, and acidifying the resulting alkali metal salt to afford a trans- Z-carboxy-l-hydroxymethyl-2-(lower alkyl)-l,2,3,4,4a,9, l0,10a-octahydrophenanthren-7-ol 7-(lower alkyl) ether.

2. As in claim 1, the process which comprises contacting G-methoxy-l-vinyl-l-tetralol with 2-methyl-4-oxacyclopentane-1,3-dione, heating the resulting 2-methyl-2-(6- methoxy l naphthyliden)ethyl-4-oxacyclopentane-1,3- dione with an acidic reagent, contacting the resulting 3- methoxy-l6-oxaestra-1,3,5(10),8(9),l4 pentaen-17-one with hydrogen in the presence of a hydrogenation catalyst, contacting the resulting 3-methoxy-l6-oxaestra-l,3,5(l0), 8(9)-tetraen-l7-one with an alkali metal hydroxide or suitable Weak acid salt, contacting the resulting alkali metal salt of trans-Z-carboxy-l-hydroxymethyl-Z-rnethyll,2,3,4,9,lO-hexahydrophenanthren-7-ol 7-methyl ether or the corresponding free acid with an alkali metal and liquid ammonia and acidifying the resulting alkali metal salt to afford trans-Z-carboxy-l-hydroxymethyl-2-methyl-l,2, 3,4,4a,9,l0,IOa-octahydrophenanthren 7 ol 7 methyl ether.

3. The process Which comprises contacting a 3-(lower alkoxy)-13fi(lower alkyl)-l6oxagona-1,3,5(l0),8(9),l4- pentaen-l7-one with an alkali metal hydroxide or suitable weak acid salt, contacting the resulting alkali metal salt of a trans-2-carboxy-l-formyl-Z-(lower alky1)-1,2,3, 4,9,10-hexahydrophenanthren-7-ol 7-(lower alkyl) ether with a suitable reducing agent, contacting the resulting alkali metal salt of a tmns-2-carboxy-l-hydroxy-methyl- 2 (lower alkyl)-1,2,3,4,9,10-hexahydrophenanthren-7-ol 7-(lower alkyl) ether or the corresponding free acid with an alkali metal and liquid ammonia and acidifying the resulting alkali metal salt to afford a trans-Z-carboxy-lhydroxymethyl-Z-(lower alkyl)-1,2,3,4,4a,9,10,l0a octahydrophenanthren-7-ol 7-(lower alkyl) ether.

4. As in claim 3, the process which comprises contacting 3-methoxy-1 6-oxaestra-1,3,5 10) ,8 (9 l4-pentaenl7-one with an alkali metal hydroxide or suitable weak acid salt, contacting the resulting alkali metal salt of trans-Z-carboxy-l-formyl 2 methyl 1,2,3,4,9,10 hexahydrophenanthren-7-ol 7-methyl ether with a suitable reducing agent, contacting the resulting alkali metal salt of trans-Z-car'ooxy-l-hydroxymethyl 2 methyl l,2,3,4,9, 10-hexahydrophenanthren-7-ol 7-methyl ether or the corresponding free acid with an alkali metal and liquid ammonia and acidifying the resulting alkali metal salt to afford trans-2-carboxy 1 hydroxymethyl 2 methyl- 1,2,3,4,4a,9,10,10a octahydrophenanthren-7-ol 7-methyl ether.

10 5. A compound of the formula (lower lower) l A l l (lower alkyl) 0 6. As in claim 5, the compound which is 2-methyl-2- (G-methoxy-l-naphthyliden)ethyl 4 oxacyclopentane-l, a 3-dione.

8. As in claim 7, the compound which is dl-3-methoxy- 16-oxaestra-l,3,5 l0) ,8 (9) ,l4-pentaen-17-one. 9. A compound of the formula 7 (lower alkyl) (lower alky )0 Q 10. As in claim 9, the compoundwhich is dl-3-methoxy- 16-oxaestra-l,3,5 l0) ,8 (9 -tetraen-l7-one.

11. A compound of the formula (lower alkyl) O O O H CH2OH (lower alkyl) 0 12. As in claim 11, the compound which is dl-trans-Z- carboxy 1 hydrOxymethyl-Z-methyl-l,2,3,4,9,l0-hexahydrophenanthrcn-7-ol 7-methyl ether.

13. A compound of the formula 14. As in claim 13, the compound which is dl-trans-Z- carboxy 1 formyl -2 -methyl-l,2,3,4,9,lO-hexahydrophenanthren-7-ol 7-methyl ether.

References Cited by the Examiner Wieland et al.; Helv. Chim. Acta., 31, 229-232, (1948).

ALEX MAZEL, Primary Examiner.

JOSEPH A. NARCAVAGE, Assistant Examiner. 

7. A COMPOUND OF THE FORMULA 